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Synlett 2008(1): 77-82  
DOI: 10.1055/s-2007-992411
LETTER
© Georg Thieme Verlag Stuttgart · New York

Microwave-Enhanced Fischer Reaction: An Efficient One-Pot Synthesis of γ-Carbolines

Jing Chen, Weiliang Chen, Yongzhou Hu*
ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Zijingang Campus, Hangzhou, 310058, P. R. of China
Fax: +86(571)88208460; e-Mail: huyz@zju.edu.cn;
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Publication History

Received 4 October 2007
Publication Date:
11 December 2007 (online)

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Abstract

γ-Carbolines were obtained in a simple one-pot Fischer reaction starting from N-acetyl-3-bromo-4-piperidone hydrobromide and substituted arylhydrazine hydrochlorides in acidic media under microwave irradiation or by a thermal process. The optimization procedures are reported in detail, and the results from microwave processes are compared with conventional ones.

Key words

γ-carbolines - N-acetyl-3-bromo-4-piperidone hydrobromide - arylhydrazine hydrochloride - Fischer reaction - microwave irradiation

    References and Notes

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16

General Procedure for the Conventional Synthesis of γ-Carbolines 5A mixture of N-acetyl-3-bromo-4-piperidone hydrobromide 6 (1 mmol; prepared according to ref.18) and substituted arylhydrazine hydrochloride 7 (1.5 mmol) in 5 mL glacial AcOH or BF3·OEt was stirred and refluxed for 12 h. After cooling down, the mixture was neutralized with aq Na2CO3 and extracted with EtOAc (3 × 20 mL). The extract was dried over anhyd Na2SO4 and concentrated in vacuo to give crude product, which was further purified by silica column chromatography (using different ratio of PE-EtOAc-EtOH as eluent according to different products).General Procedure for the Microwave-Assisted Synthesis of γ-Carbolines 5A mixture of N-acetyl-3-bromo-4-piperidone hydrobromide (6, 1 mmol) and substituted arylhydrazine hydrochloride 7 (1.5 mmol) was placed in a microwave test tube (10 mL) containing a magnetic stirring bar and 5 mL glacial AcOH or BF3·OEt. The test tube was placed in the microwave cavity (InitiatorTM 2.0, Biotage, 400 W, 2450 MHz) and subjected to microwave irradiation at 230 °C for 5 min. After completion of the reaction, the tube was removed and cooled to r.t. The following workup and purification of the crude product was quite the same as above.

17

All compounds gave satisfactory analytical and spectral data. Data for selected compounds are as follows:6-Bromo-γ-carboline (5f): white powder; mp 282-283 °C (PE-EtOAc-EtOH). 1H NMR (400 MHz, DMSO-d 6): δ = 11.87 (s, NH), 9.38 (s, 1 H), 8.50 (d, J = 1.6 Hz, 1 H), 8.45 (d, J = 5.6 Hz, 1 H), 7.61 (dd, J = 8.8, 1.6 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 1 H), 7.49 (d, J = 5.6 Hz, 1 H). 13C NMR (100 MHz, DMSO-d 6): δ = 144.8, 144.0, 143.2, 138.4, 129.1, 123.3, 122.7, 118.6, 113.5, 112.2, 106.7. ESI-MS: m/z = 247 [M + 1]+. Anal. Calcd for C11H7BrN2: C, 53.47; H, 2.86; N, 11.34. Found: C, 53.57; H, 2.67; N, 11.23.8-Chloro-γ-carboline (5h): white powder; mp 219-220 °C (PE-EtOAc-EtOH). 1H NMR (400 MHz, DMSO-d 6): δ = 12.15 (br s, NH), 9.38 (s, 1 H), 8.48 (d, J = 5.6 Hz, 1 H), 8.23 (d, J = 8.0 Hz, 1 H), 7.57 (d, J = 8.0 Hz, 1 H), 7.53 (d, J = 5.6 Hz, 1 H), 7.31 (t, J = 8.0 Hz, 1 H). 13C NMR (100 MHz, DMSO-d 6): δ = 145.0, 144.0, 143.3, 136.6, 126.0, 122.8, 121.2, 119.6, 119.5, 115.8, 106.9. ESI-MS: m/z = 203 [M + 1]+. Anal. Calcd for C11H7ClN2: C, 65.20; H, 3.48; N, 13.82. Found: C, 65.25; H, 3.25; N, 13.89.